A reduction of nicotine receptors is reported in Alzheimer's disease (AD) and, conversely, an increase in the number of these receptors is reported in smokers. Imaging these receptors will therefore offer diagnostic capabilities for the study of both AD as well as nicotine dependency. At University of California-Irvine (UCI), we have two major programs: one in AD within the Center for Aging and Dementia and the other a program on studies related to nicotine dependence. The goal of this application is to develop selective alpha4beta2 nicotine acetylcholinergic receptor (a4b2 nAChR) radiopharmaceuticals for use in human PET imaging at the Brain Imaging Center at UCI. This will support collaborative research studies in the above two areas of interest at UCI. This research will also support investigations on other disorders such as Parkinson's disease and schizophrenia. Over the three-year period, our goal is to design and develop quantitative methods for a4b2 nAChR PET imaging studies using an agonist and an antagonist. We have successfully identified structural features in the pyridylether class of compounds that enable development of an antagonist and enhance the binding kinetics of agonists. Our preliminary efforts in developing agents with these properties have been promising. In this application developmental studies of 3 compounds will be carried out. These are putative agonist 2-18F-fluoro-3-[2-(3-(S)-pyrrolinylmethoxy)]pyridine (18F-nifene), and putative antagonists 5-(3 -18F-fluoropropyl)-(3-[2-(S)-pyrrolidinyl)methoxy]pyridine (18F-nifrolidine) and 5-(3 -18F-fluoropropyl)-(3-[2-(3-(S)-pyrrolinylmethoxy)]pyridine (18F-nifrolene). We hypothesize that 18F- nifrolene will have similar, faster kinetics like 18F-nifene. We propose to carry out pharmacological characterization of these compounds, optimize radiosynthesis, evaluate feasibility of quantitative PET studies and conduct test-retest studies. Based on these results radiation dosimetry measures in male and female rats with 18F-nifene as the agonist and either 18F-nifrolidine or 18F-nifrolene as the antagonist will be carried out. Upon complete characterization toxicity data of two agents will be obtained in order to file for an expedited investigational new drug application. Thus the outcome of this 3-year application would be to have an agonist and an antagonist for PET human imaging studies of the a4b2 receptor system. Continuation of this application will then study the role of these receptors in AD and nicotine dependency.